Moulding D A, Quayle J A, Hart C A, Edwards S W
School of Biological Sciences, Life Sciences Building; and the Department of Medical Microbiology, University of Liverpool, Liverpool, UK.
Blood. 1998 Oct 1;92(7):2495-502.
Human neutrophils possess a very short half-life because they constitutively undergo apoptosis. Cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), and other agents can rescue neutrophils from apoptosis but the molecular mechanisms involved in this rescue are undefined. Here, we show by Western blotting that human neutrophils do not express Bcl-2 or Bcl-X but constitutively express Bax. However, cellular levels of these proteins are unaffected by agents which either accelerate or delay neutrophil apoptosis. In contrast, neutrophils express the antiapoptotic protein Mcl-1 and levels of this protein correlate with neutrophil survival. Thus, cellular levels of Mcl-1 decline as neutrophils undergo apoptosis and are enhanced by agents (eg, GM-CSF, interleukin-1beta, sodium butyrate, and lipopolysaccharide) that promote neutrophil survival. Neutrophils only possess few, small mitochondria, and much of the Mcl-1 protein seems to be located in nuclear fractions. These observations provide the first evidence implicating a Bcl-2 family member in the regulation of neutrophil survival. Moreover, this work also provides a potential mechanism whereby cytokine-regulated gene expression regulates the functional lifespan of neutrophils and hence their ability to function for extended time periods during acute inflammation.
人类中性粒细胞的半衰期非常短，因为它们会持续发生凋亡。细胞因子，如粒细胞巨噬细胞集落刺激因子（GM-CSF）和其他因子可以挽救中性粒细胞免于凋亡，但这种挽救所涉及的分子机制尚不清楚。在这里，我们通过蛋白质印迹法表明，人类中性粒细胞不表达Bcl-2或Bcl-X，但持续表达Bax。然而，这些蛋白质的细胞水平不受加速或延迟中性粒细胞凋亡的因子的影响。相反，中性粒细胞表达抗凋亡蛋白Mcl-1，并且该蛋白的水平与中性粒细胞的存活相关。因此，随着中性粒细胞发生凋亡，Mcl-1的细胞水平下降，并被促进中性粒细胞存活的因子（如GM-CSF、白细胞介素-1β、丁酸钠和脂多糖）增强。中性粒细胞仅拥有少量、小型的线粒体，并且大部分Mcl-1蛋白似乎位于细胞核组分中。这些观察结果提供了首个证据，表明Bcl-2家族成员参与中性粒细胞存活的调节。此外，这项工作还提供了一种潜在机制，通过该机制细胞因子调节的基因表达调节中性粒细胞的功能寿命，从而调节它们在急性炎症期间长时间发挥功能的能力。
